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Drug UpdateUrocortin, a novel inodilator in development?
Reviewer: K. W. Tim Park, MD Boston, MA
For years, corticotropin-releasing factor (CRF) has been accepted as the primary hormone involved in the mammalian response to stress. In addition to its central nervous system actions to stimulate pituitary release of adrenocorticotropic hormone (ACTH) and adrenal release of steroid hormones, CRF also increases blood pressure. However, the normal serum levels of CRF are very low and it has been a puzzle how CRF exerts its peripheral effects. Part of the answer to this puzzle was provided by recent discoveries of (a) peripheral expression of a CRF receptor type 2b (CRF-R2b) and (b) a novel peptide urocortin. Whereas CRF receptors type 1, type 2a, and type 2g were expressed primarily in the brain, CRF-R2b was present in both brain and peripheral tissues, including myocardium, coronary arterioles, and the gastrointestinal tract. Urocortin is a CRF-related peptide, that at least in animals, is expressed in cardiac myocytes and coronary vascular smooth muscle cells. Urocortin strongly binds and stimulates CRF-R2b receptors (1-3). Plasma levels of urocortin have been found to be quite low suggesting that it may act as a paracrine hormone, rather than a circulating hormone. The cardiovascular actions of urocortin have several potential therapeutic applications. First, in both rats and sheep, urocortin has been found to have a strong inotropic action, as measured by maximum aortic flow and aortic dF/dt (1,4). This positive inotropic action was caused by increases in myocyte cyclic AMP, but was not inhibited by b-adrenergic blockade, NO synthesis blockade, or Na+-K+-ATPase blockade (1,5). The inotropic action of urocortin in sheep lasted for up to 24 hours after a single intravenous injection of 100 mg (6). Second, peripherally-administered urocortin was a potent vasodilator in rats, probably by its action on the mesenteric vascular beds, and was three times more potent than CRF in this regard (3). In sheep, urocortin has also been demonstrated to increase coronary conductance and coronary blood flow (6). Because of systemic vasodilation, urocortin may lead to reflex tachycardia. Third and perhaps most interesting, urocortin has been shown to have a protective effect on isolated myocytes and isolated hearts subject to hypoxic/ischemic injury when it was administered either prior to ischemia or at the time of reperfusion (7). This protective effect appeared to be mediated by MAP kinase-dependent pathways. Furthermore, secretion of natriuretic peptides (atrial natriuretic peptide and brain natriuretic peptide), which have been proposed to have a protective function during heart failure, was increased by urocortin (8), further indicating that urocortin may be an endogenous cardioprotective agent. Enthusiasm for urocortin must await clinical trials and development of the drug. In addition, side effect profiles of the chemical must be worked out. Urocortin is proinflammatory and activates mast cells. Although mast cell activation could be prevented by pretreatment with the mast cell stabilizer cromolyn (9). Urocortin may also be anxiogenic (10). With proper prophylaxis against potential side effects, urocortin may be the next agent with cardioprotective and inotropic actions on the horizon. References:
1. Parkes DG, May CN. Urocortin: a novel player in cardiac control. News Physiol Sci 2000; 15:264-8 2. Perrin M, Donaldson C, Chen R, et al. Identification of a second corticotropin-releasing factor receptor gene and characterization of a cDNA expressed in the heart. Proc Natl Acad Sci USA 1995; 92:2969-73 3. Vaughan J, Donaldson C, Bittencourt J, et al. Urocortin, a mammalian neuropeptide related to urotensin 1 and corticotropin-releasing factor. Nature 1995; 378:287-92 4. Terui K, Higashiyama A, Horiba N, et al. Coronary vasodilation and positive inotropism by urocortin in the isolated rat heart (Abstract). 81st Annual Meeting of the Endocrine Society, San Diego, CA, 1999, p 269. 5. Heldwein K, Redick D, Schmidhuber H, et al. Effects of corticotropin-releasing hormone receptor expression and functional coupling in neonatal cardiac myocytes and AT-1 cells. Endocrinology 1996; 137:331 6. Parkes DG, Vaughan J, Rivier J, et al. Cardiac inotropic actions of urocortin in conscious sheep. Am J Physiol 1997; 272:H2115-22 7. Brar BK, Jonassen AK, Stephanou A, et al. Urocortin protects against ischemic and reperfusion injury via a MAPK-dependent pathway. J Biol Chem 2000; 275:8508-14 8. Ikeda K, Tojo K, Sato S, et al. Urocortin, a newly identified corticotropin-releasing factor-related mammalian peptide, stimulates atrial natriuretic peptide and brain natriuretic peptide secretions from neonatal rat cardiomyocytes. Biochem Biophys Res Commun 1998; 250:298-304 9. Singh LK, Boucher W, Pang K, et al. Potent mast cell degranulation and vascular permeability triggered by urocortin through activation of corticotropin-releasing hormone receptors. J Pharmacol Exp Ther 1999; 288:1349-56 10. Moreau JL, Kilpatrick G, Jenck F. Urocortin,
a novel neuropeptide with anxiogenic-like properties. Neuro-report
1997; 8:1697-701
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